Transport of messenger RNA from the nucleus to the cytoplasm

Cole, Charles N.; Scarcelli, John J.

doi:10.1016/j.ceb.2006.04.006

Cited by 114 publications

(81 citation statements)

References 57 publications

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“…The translocation of mRNA from the nuclear site of transcription to the cytoplasmic site of translation appears to be a highly regulated process that is mediated by numerous RNA-binding proteins, some of which act as adaptors to access specific nuclear export pathways, thereby assembling exportcompetent messenger RNP complexes [29,51,52]. Generally, the nuclear export of bulk poly(A) 1 mRNA is mediated in metazoans by the transport receptor NXF1/Tap, together with its small cofactor Nxt1/p15 (reviewed in detail in [30,[53][54][55]).…”

Section: Discussionmentioning

confidence: 99%

“…The spatial and temporal recruitment of varying RNA-binding proteins onto individual mRNA results in highly dynamic RNP complexes [48]. Thus, the individual composition of distinct RNA-binding proteins on a given mRNA determines the final destiny of this transcript, resulting in translation and/or degradation [49,50].The translocation of mRNA from the nuclear site of transcription to the cytoplasmic site of translation appears to be a highly regulated process that is mediated by numerous RNA-binding proteins, some of which act as adaptors to access specific nuclear export pathways, thereby assembling exportcompetent messenger RNP complexes [29,51,52]. Generally, the nuclear export of bulk poly(A) 1 mRNA is mediated in metazoans by the transport receptor NXF1/Tap, together with its small cofactor Nxt1/p15 (reviewed in detail in [30,[53][54][55]).…”

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confidence: 99%

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Phosphorylation of the HuR ligand APRIL by casein kinase 2 regulates CD83 expression

et al. 2009

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Fully mature DC and, to a lesser extent, activated T and B cells express CD83, a surface molecule that appears to fulfil an important role in efficient T-cell activation. Recently, it has been shown that CD83 mRNA is transported from the nucleus to the cytoplasm by an uncommon route, involving the cellular RNA-binding protein HuR and the nuclear export receptor CRM1. Moreover, the shuttle phosphoprotein APRIL (ANP32B) has been shown to be required for HuR-mediated nucleocytoplasmic translocation of the CD83 mRNA by acting as an adaptor that links HuR and CRM1. Here, we are able to report that casein kinase 2 (CK2) phosphorylates APRIL on residue threonine244 (Thr 244 ) and demonstrate that the CK2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes CD83 expression in activated Jurkat T cells by interfering with the nucleocytoplasmic translocation of CD83 mRNA. Depletion and knockdown studies demonstrate that the CK2 a 0 subunit is necessary for this regulation, whereas the CK2 a subunit seems to be dispensable. Taken together, the data presented significantly extend our knowledge of the complex regulation of CD83 mRNA processing and provides a novel strategy to interfere with CD83 expression.Key words: APRIL . Casein kinase 2 . CD83 . HuR . Leukocytes IntroductionMature DC are capable of sensitizing even naïve CD4 1 and CD8 1 T cells, and are therefore frequently termed ''nature's adjuvant''. Immature DC reside in the peripheral tissues and upon uptake of antigen and exposure to inflammatory stimuli, they migrate to the peripheral lymph nodes, where now fully matured, they induce antigen-specific T-cell response [1][2][3][4]. The DC maturation process includes the modulation of chemokine and chemokine receptors, as well as the up-regulation of several cytokines, costimulatory and adhesion molecules [5].Human CD83 serves as a major marker molecule for mature DC that belongs to the immunoglobulin super family [6,7]. This membrane-bound protein is also expressed, although to a significant lower extent, on activated T and B cells [7][8][9][10]. Moreover, a soluble form of CD83 is detectable at low levels in sera derived from healthy individuals, whereas in contrast, elevated levels are present in patients suffering from certain hematological malignancies [8,11]. Notwithstanding the fact that accumulating experimental evidence suggests that CD83 plays an important functional role in the regulation of DCmediated T-cell-specific immune response [12][13][14][15][16][17][18][19], the exact function of CD83 remains poorly understood [20][21][22]. Nevertheless, various disease-related findings suggest that CD83 holds great potential for future therapeutic application [23]. For example, EAE can be prevented in mice by applying a soluble form of CD83 [24]. Likewise, in rats, a positive therapeutic effect on experimental autoimmune myasthenia gravis has been reported by application of pentoxifylline, a drug that apparently interferes with CD83 expression [25,26]. Furthermore, CD83 1 DC were found to localize i...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Phosphorylation of the HuR ligand APRIL by casein kinase 2 regulates CD83 expression

et al. 2009

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“…These intimate connections, as well as other well documented links between various steps in RNA biogenesis (40,41), suggest that pore proteins may be involved from an early point in RNA production. Thus, rather than envisioning a fully packaged mRNP encountering pore proteins only at the time of translocation through the nuclear pore complex, we must consider the role of pore proteins during transcription, processing, Table 1 for sequences.…”

Section: Discussionmentioning

confidence: 99%

Sequence Preference in RNA Recognition by the Nucleoporin Nup153

Ball¹,

Dimaano²,

Bilak

et al. 2007

Journal of Biological Chemistry

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The vertebrate nuclear pore protein Nup153 contains a novel RNA binding domain. This 150-amino acid region was previously found to bind preferentially to a panel of mRNAs when compared with structured RNAs, such as tRNA, U snRNA, and double-stranded RNA. The ability to broadly recognize mRNA led to the conclusion that the Nup153 RNA binding domain confers a general affinity for single-stranded RNA. Here, we have probed Nup153 RNA recognition to decipher how this unique RNA binding domain discriminates between potential targets. We first mapped the binding determinant within an RNA fragment that associates relatively robustly with the Nup153 RNA binding domain. We next designed synthetic RNA oligonucleotides to systematically delineate the features within this minimal RNA fragment that are key to Nup153 RNA-binding domain binding and demonstrated that the binding preferences of Nup153 do not reflect general preferences of an mRNA/single-stranded RNA-binding protein. We further found that the association between Nup153 and a cellular mRNA can be attributed to an interaction with specific subregions of the RNA. These results indicate that Nup153 can discriminate between mRNA and other classes of RNA transcripts due in part to direct recognition of a loose sequence motif. This information adds a new dimension to the interfaces that can contribute to recognition in mRNA export cargo selection and fate.Nuclear pore complexes are macromolecular structures that bridge the inner and outer nuclear membranes to form a channel for nucleocytoplasmic traffic (1-3). Recent molecular characterization of pore complexes has revealed that they are comprised of only ϳ30 different proteins (4, 5), with multiples of eight copies of each protein forming the 8-fold symmetric structure characteristic of the nuclear pore complex. A small number of nucleoporins are restricted in localization to either the nuclear or cytoplasmic side of the pore, and their skewed distribution contributes to distinct features on each of these faces: the nuclear basket structure and the cytoplasmic filaments. The observation that repetitive arrangement of a relatively limited number of proteins creates the elaborate pore structure suggests that each nucleoporin carries out multiple tasks, from providing structural scaffolding to contacting diverse cargo-receptor complexes as they transit through the pore.The paradigm of multifunctional pore components is well illustrated by the nucleoporin Nup153. This pore protein plays roles in both import and export pathways (6 -11). Consistent with this, Nup153 interacts with various transport receptors (7,(12)(13)(14)(15)(16)(17)(18), as well as with specific cargo (6, 10). Nup153 has also been found to be essential for the localization of other pore components (19) and is specifically thought to anchor the basket constituent TPR (20). Somewhat paradoxically, Nup153 has been shown to be dynamically localized to the nuclear pore (21,22). This apparent contradiction, as well as the multiple roles implicated for Nup153, ma...

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“…As noted above, this comparison of in vitro and in vivo activities points to the presence of unidentified modifying activities present in the intact cell. The studies described herein do not suggest the identity of these proteins, but candidates might include components of the replete RNAi machinery including proteins responsible for RISC loading, the ATP-dependent RNA helicase necessary for product release likely to be found in P-bodies, as well as proteins present in translational initiation complexes, and RNA helicases, such as Dbp5 in the nuclear pore complex whose function is thought to strip proteins from the mRNA as it exists the nucleus (32)(33)(34). It is equally clear that because delivery of AON was not a factor in these in vivo experiments (21), the AONЈs activity must have been impaired by what are likely other cis-regulator proteins, as was illustrated by results presented in Fig.…”

Section: Discussionmentioning

confidence: 99%

Effects of local mRNA structure on posttranscriptional gene silencing

Rudnick¹,

Swaminathan²,

Sumaroka

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Antisense oligodeoxynucleotides (AONs) and short interfering RNAs (siRNAs) effect posttranscriptional gene silencing (PTGS) by hybridizing to an mRNA and then directing its cleavage. To understand the constraints that mRNA structure imposes on AON-vs. siRNA-mediated PTGS, AON-and siRNA-mediated cleavage of defined mRNA structures was monitored in Drosophila embryo whole-cell lysates. We observed that AON-directed cleavage was Ϸ3-fold faster than cleavage with a siRNA directed to the same target site. Furthermore, and unexpectedly, AON-mediated cleavage was found to be much less fastidious with respect to target sequence accessibility, as measured by the presence of unpaired nucleotides, than a corresponding siRNA. Nonetheless, in vivo, siRNAs silenced their mRNA target at least 2-fold more efficiently than the corresponding AON. These seemingly contradictory results suggested that additional, as yet undefined factors play an important role in regulating PTGS efficiency in vivo. We used a well defined RNA-binding protein, ␣CP, and its corresponding highaffinity RNA-binding site to explore this hypothesis. We found that prebound ␣CP effectively blocked AON-mediated cleavage of the RNA-binding site compared with cleavage of the site in the absence of ␣CP. We conclude that higher-order structures formed by RNA and bound proteins play an important role in determining the efficiency of AON-directed PTGS. We hypothesize that strategies aimed at removing RNA-binding proteins might significantly improve AON-mediated PTGS in vivo.antisense ͉ oligodeoxynucleotide ͉ siRNA

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Transport of messenger RNA from the nucleus to the cytoplasm

Cited by 114 publications

References 57 publications

Phosphorylation of the HuR ligand APRIL by casein kinase 2 regulates CD83 expression

Phosphorylation of the HuR ligand APRIL by casein kinase 2 regulates CD83 expression

Sequence Preference in RNA Recognition by the Nucleoporin Nup153

Effects of local mRNA structure on posttranscriptional gene silencing

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